Method for making 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone)

ABSTRACT

The present invention relates to methods for making racemic 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone and (+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone.

This is a divisional of application Ser. No. 11/206,144, filed Aug. 18,2005, which is a continuation of application Ser. No. 10/400,780, filedMar. 27, 2003, now U.S. Pat. No. 6,949,653 which claims benefit ofapplication No. 60/368,609, filed Mar. 29, 2002, the disclosures ofwhich are incorporated by reference in their entirety herein.

FIELD OF THE INVENTION

The present invention relates to methods for making racemic2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinoneand(+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone.

BACKGROUND OF THE INVENTION

The compound(+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone,also called pagoclone, is a GABA (gamma amino butyric acid) receptorligand that is presently being evaluated in human clinical studies forthe treatment of generalized anxiety disorder and panic disorder.

Pagoclone can also be used to treat obsessive-compulsive disorder, acutestress disorder, post traumatic stress disorder, social anxietydisorder, somatization disorder, specific social phobia, premenstrualdysphoric disorder, anxiety associated with a medical condition,adjustment disorder with anxious mood, dysthymia, specific phobia orfibromyalgia.

U.S. Pat. No. 4,960,779, issued Oct. 2, 1990, relates to pyrrolederivatives and compositions comprising pyrrole derivatives, includingpagoclone, and to methods of producing an anxiolytic, hypnotic,anticonvulsant, antiepileptic or muscle relaxant therapeutic effect thatcomprises administering a pyrrole derivative.

The present invention provides a convenient method for making racemic2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinoneand(+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone.

SUMMARY OF THE INVENTION

The present invention provides methods of making racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the methods comprising the steps of:

a) reacting 2,6-diaminopyridine with malic acid and sulfuric acid toform 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt;

b) reacting 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt witha phthalyl reactant in a solvent to form phthalimidyl naphthyridine 2

c) reacting phthalimidyl naphthyridine 2 with a chlorinating agent toform chloride 3

d) reacting chloride 3 with a reducing agent to form hydroxyindolinone 4

e) reacting hydroxyindolinone 4 with a 5-methyl-2-oxo-hexyl derivativeto form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

In a preferred embodiment of the methods, in step b the phthalylreactant is phthalic anhydride; in step c the chlorinating agent isphosphorus oxychloride; in step d the reducing agent is potassiumborohydride; and in step e the 5-methyl-2-oxo-hexyl derivative is[(5-methyl-2-oxo)-hexyl]triphenylphosphonium bromide.

Also provided are methods of making(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the methods comprising the steps of:

a) reacting 2,6-diaminopyridine with malic acid and sulfuric acid toform 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt;

b) reacting 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt witha phthalyl reactant in a solvent to form phthalimidyl naphthyridine 2

c) reacting phthalimidyl naphthyridine 2 with a chlorinating agent toform chloride 3

d) reacting chloride 3 with a reducing agent to form hydroxyindolinone 4

e) reacting hydroxyindolinone 4 with a 5-methyl-2-oxo-hexyl derivativeto form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone;and

f) resolving racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinoneto provide(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

In a preferred embodiment of the methods wherein the racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinoneis resolved to provide(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the resolution comprises the steps of:

g) reacting racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinonewith a base to form acid 6

h) reacting acid 6 with (+)-ephedrine to form salt 6a

i) reacting salt 6a with an amide forming reagent to form(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

In a preferred embodiment of the resolution, the base in step g ispotassium hydroxide; and in step i the amide forming reagent iscarbonyldiimidazole.

Also provided is the compound 2-amino-7-hydroxy-1,8-naphthyridinesulfuric acid salt.

Also provided are methods of making 2-amino-7-hydroxy-1,8-naphthyridinesulfuric acid salt, the methods comprising the step of reacting2,6-diaminopyridine with malic acid and sulfuric acid to form2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt.

Also provided are methods of making racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the methods comprising the steps of:

a) reacting 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt witha phthalyl reactant in a solvent to form phthalimidyl naphthyridine 2

b) reacting phthalimidyl naphthyridine 2 with a chlorinating agent toform chloride 3

c) reacting chloride 3 with a reducing agent to form hydroxyindolinone 4

d) reacting hydroxyindolinone 4 with a 5-methyl-2-oxo-hexyl derivativeto form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

Also provided are methods of making racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the methods comprising the steps of:

a) reacting phthalimidyl naphthyridine 2

with a chlorinating agent to form chloride 3

b) reacting chloride 3 with a reducing agent to form hydroxyindolinone 4

c) reacting hydroxyindolinone 4 with a 5-methyl-2-oxo-hexyl derivativeto form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

Also provided are methods of making racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the methods comprising the steps of:

a) reacting chloride 3

with a reducing agent to form hydroxyindolinone 4

b) reacting hydroxyindolinone 4 with a 5-methyl-2-oxo-hexyl derivativeto form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

Also provided are methods of making racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the method comprising the step of reacting hydroxyindolinone 4

with a 5-methyl-2-oxo-hexyl derivative to form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for making racemic2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinoneand then resolving the racemic2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinoneto provide(+)-2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone,which is called pagoclone.

The present method is illustrated in Scheme 1 below.

Step 1

In step 1 of the method, commercially available 2,6-diaminopyridine(e.g., Aldrich, Milwaukee, Wis.) is reacted with malic acid in sulfuricacid to provide 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt.It is noted that 2-amino-7-hydroxy-1,8-naphthyridine free base isdescribed in S. Carboni et al., Gazz. Chim. Ital., 95, 1498 (1965).

2-Amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt (1)

2,6-Diaminopyridine (167 g, 1.53 mol) was added in portions to sulfuricacid (1.14 kg, 11.7 mol) at 40° C. The temperature of the solution wasmaintained at 40-50° C. during the addition with a water bath. When allof the 2,6-diaminopyridine was dissolved, the solution was cooled to 20°C. Malic acid (206 g, 1.53 mol) was added to the solution and thereaction mixture was gradually heated to 110° C. over 90 minutes. Themixture was stirred at 110-120° C. for one hour, cooled to roomtemperature, and poured slowly into a cold brine solution (167 g NaCl,1.6 kg ice water). The quenched mixture was stirred at room temperaturefor one hour and filtered. The material was washed with hexanes (335 mL)and dried at 60° C. under vacuum to yield2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt as a yellowsolid: 354 g, 89% yield; MS (DCI) M+1 at 162, 100%; ¹H NMR (200 MHz,DMSO-d₆) δ 4.32 (br. s, 5H, —OH, —NH₂, H₂SO₄), 6.41 (d, J=9.0 Hz, 1H,C6), 6.56 (d J=9.0 Hz, 1H, C5), 7.85 (d J=6.6 Hz, 1H, C3), 7.91 (d J=6.6Hz, 1H, C4).

Steps 2-4

In step 2, 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt isreacted with a phthalyl reactant to form phthalimidyl naphthyridine 2

The reaction is typically conducted in a solvent, preferably aceticacid, and a base is added. The base is selected from the bases that arestrong enough to deprotonate the sulfuric acid salt, but which do notdestroy the phthalyl reactant. Suitable bases include di, tri and arylsubstituted amines, and a preferred base is triethylamine. The phthalylreactant is a reagent that reacts with the amine group of the2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt to provide thephthalimidyl naphthyridine 2. Examples of suitable phthalyl reactantsinclude phthalyl chloride, phthalic acid and phthalic acid esters. Apreferred phthalyl reactant is phthalic anhydride, and a preferred basefor use with phthalic anhydride is triethylamine. The phthalimidylnaphthyridine 2 can also be made in a procedure analogous to thatdisclosed in U.S. Pat. No. 4,220,646.

In step 3, phthalimidyl naphthyridine 2 is reacted with a chlorinatingagent to form chloride 3

Chlorinating agents that convert the hydroxy group of the phthalimidylnaphthyridine to chlorine are required. Suitable chlorinating agentsinclude, but are not limited to, thionyl chloride, cyanuric chloride,hydrochloric acid, phosphorus pentachloride, phosphorus trichloride andoxalyl chloride. A preferred chlorinating agent is phosphorusoxychloride. The chlorination can typically be run in a polar, aproticsolvent or can be run in neat phosphorus oxychloride. A preferredchlorination comprises the use of acetonitrile as the solvent andphosphorus oxychloride as the chlorinating agent. A catalytic amount ofdimethlyformaminde is also used. The chloride 3 can also be made in aprocedure analogous to that disclosed in U.S. Pat. No. 4,220,646.

In step 4, the chloride 3

is reduced with a reducing agent to provide hydroxyindolinone 4

The reducing agent can be any compound that reduces the carbonyl groupon the phthalyl ring to an alcohol. Examples of preferred reducingagents include salts of borohydride, borane and substituted boranes. Apreferred borohydride salt is potassium borohydride. The solvent can bean alcohol or an ether or any other solvent that is compatible with thechloride and the reducing agent. When the reducing agent is potassiumborohydride, a preferred solvent is water. It is noted that steps 3 and4 can be run sequentially without isolation of intermediate products.The hydroxyindolinone 4 can also be made in a procedure analogous tothat disclosed in U.S. Pat. No. 4,220,646.

2-N-Phthalimidyl-7-hydroxy-1,8-naphthyridine (2)

2-Amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt (5.5 g) andphthalic anhydride (8.3 g) were stirred in acetic acid (27 mL). Thereaction was cooled in an ice bath while triethylamine (11 mL) was addedat a rate such that the batch temperature did not exceed 30° C. Afterall of the triethylamine was added, the reaction was heated at about115° C. for 5 hrs. The reaction was cooled to about 25° C. and quenchedwith methanol (30 mL). The product was filtered and washed with methanol(30 mL). The product was dried under vacuum at 60° C. This afforded 5.9g of 2-N-phthalimidyl-7-hydroxy-1,8-naphthyridine 2 (95% yield). ¹H-NMR:δ 12.45 (s, 1H), 8.43 (d, J=8.1 Hz, 1H), 8.09 (m, 5H), 7.49 (d, J=8.1,1H), 6.74 (d, J=9.5, 1H); CI (MS) M+1 at 292, 100%.

N-(7-Chloro-1,8-naphthyridin-2-yl)3-hydroxyindolinone (4)

Phosphorus oxychloride (83.9 g, 547 mmol) was added to a refluxingslurry of 2-N-phthalimidyl-7-hydroxy-1,8-naphthyridine (140 g, 481 mmol)in acetonitrile (1.05 L) and N,N-dimethylformamide (8.87 g, 121 mmol).The reaction mixture was refluxed for 4 hours and cooled to 3° C.Aqueous potassium hydroxide (45%, 109 mL, 1.28 mol) was added over 30minutes, keeping the internal temperature below 25° C. The mixture wascooled to 3° C. Potassium borohydride (84 g, 1.56 mol) was added slowlyas a solution in water (700 mL), maintaining the reaction temperaturebelow 35° C. The mixture was heated to 35-40° C. for 1 hour and cooledto room temperature. Aqueous acetic acid (385 mL acetic acid, 350 mLwater) was added followed by glacial acetic acid (875 mL). The mixturewas stirred for 15 minutes and filtered. The material was washed withwater (350 mL), methanol (350 mL), water (350 mL) and methanol (350 mL).It was dried at 60° C. under vacuum to yieldN-(7-chloro-1,8-naphthyridin-2-yl)3-hydroxyindolinone as a light yellowsolid: 140.1 g, 94% yield; MS (DCI) M+1 at 312, 100%; ¹³C NMR (101 MHz,DMSO-d₆) δ 80.74 (C2) 115.98 (C19) 119.068 (C17) 121.91 (C15) 123.39(C9) 124.10 (C6) 129.90 (C8) 130.23 (C4) 133.90 (C7) 139.40 (C18) 140.53(C16) 144.45 (C3) 152.69 (C12) 153.06 (C10) 153.77 (C14) 166.43 (C5).

Step 5

In step 5, N-(7-chloro-1,8-naphthyridin-2-yl)3-hydroxyindolinone isreacted with a 5-methyl-2-oxo-hexyl derivative to form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.The 5-methyl-2-oxo-hexyl derivative can be any derivative of5-methyl-2-oxo-hexane that provides for racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.A preferred 5-methyl-2-oxo-hexyl derivative is a[(5-methyl-2-oxo)-hexyl]triphenylphosphonium halide, with the bromidebeing preferred. The synthesis of[(5-methyl-2-oxo)-hexyl]triphenylphosphonium bromide is illustratedbelow. The reaction is typically run in an aprotic solvent at atemperature greater than or equal to about 100° C., and the reactionutilizes a base that is capable of deprotonating the phosphonium salt. Apreferred base is sodium carbonate. Examples of additional suitablebases are carbonate salts, hydroxide salts and alkoxide salts.

Racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone(5).

To a reactor was charged water (330 L), sodium carbonate (34 kg),[(5-methyl-2-oxo)-hexyl]triphenylphosphonium bromide (10) (99 kg), andxylenes (390 kg). The two-phase system was stirred for 30 minutes at 20°C. The aqueous layer was removed andN-(7-chloro-1,8-naphthyridin-2-yl)3-hydroxyindolinone (159 kg) wasadded. The reaction was heated to 136° C. (with distillation of residualwater) and held at that temperature for 24 hours. The reaction wascooled to 90° C. and the xylenes were removed via vacuum distillation.To the residue was charged isopropanol (650 L). The slurry was heated toreflux, cooled to less than 5° C., and isolated by filtration. Each loadwas washed with isopropanol (200 L) and methanol (100 L). Vacuum dryingat 60° C. afforded 170 kg (82% yield) of crystallineracemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone.APCI/MS: M+H⁺ at 408, 100%. M.P. 173-4° C.

[(5-Methyl-2-oxo)-hexyl]triphenylphosphonium bromide (10)

A solution of methanol (760 mL) and 5-methy-2-hexanone (9), which can beobtained from Eastman Chemical Company, Kingsport, Tenn., (152 mL, 1.15mol) was cooled to 0-5° C. Bromine (53 mL, 1.03 mol) was added in oneportion. The reaction was stirred at about 5° C. for 50 minutes. Afterthe exotherm was completed (about 90 minutes), the reaction was quenchedwith water (132 mL) and stirred for about 30 minutes. Methyl tert-butylether (MTBE, 1325 mL) was added. The reaction was washed with 700 mLbrine solution (238 g NaCl dissolved in 1325 mL H₂O). The organic layerwas then washed with 700 mL sodium bicarbonate solution (31.8 g NaHCO₃in 663 mL H₂O). The organic layer was then washed with another brinesolution as above. The solvent was removed under vacuum and additionalMTBE (663 mL) was added to the remaining organic residue. This MTBE wasalso removed under vacuum. The residual oil was then dissolved in MTBE(340 mL).

Triphenylphosphine (270.2 g, 1.03 mol) was dissolved in MTBE (340 mL).The bromo ketone solution was added to this solution and allowed toreact at 20° C. for 16 hours. The resulting white precipitate wasfiltered and dried under vacuum at 40° C. This afforded 273.1 g (58%yield) of [(5-methyl-2-oxo)-hexyl]triphenylphosphonium bromide. ¹H-NMR:δ 7.87 (m, 15H), 5.66 (dd, J=2.9, 12.8, 2H), 2.71 (m, 2H), 1.35 (m, 3H),0.80 (d, J=6.2, 6H); CI (MS) M at 455, 100%.

[(5-Methyl-2-oxo)-hexyl]triphenylphosphonium bromide can also be made ina method analogous to that disclosed in U.S. Pat. No. 5,532,228.

Step 6

In step 6, the lactam ring ofracemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinoneis opened to formracemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoicacid. This type of reaction is described in U.S. Pat. No. 5,498,716.

Racemic-2-[1-(7-Chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoicacid (6).

To a reactor was chargedracemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone(170 kg), 1,2-dimethoxyethane (730 L), tetrahydrofuran (THF, 990 L). Theslurry was heated to 30° C. and a solution of potassium hydroxide (140Kg) in water (1730 L) was added. The slurry was stirred at 34° C. for 34hours. The solution was cooled to 20° C. and the lower aqueous layer wasremoved and replaced with water (1000 L). The solution was adjusted topH 9.0 with 4N hydrochloric acid. The solution was vacuum distilled at30° C. to remove the THF. Water (550 L) was added and the pH of thereaction was adjusted to 11.5 with 2N potassium hydroxide. The solutionwas filtered to remove residualracemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone.To the liquors was added methylene chloride (1200 L) and the pH wasadjusted to 1.4 with 4N HCl. The aqueous layer was removed. The organiclayer was washed with water (700 L) and the water was discarded. Theorganic layer was concentrated under vacuum and replaced with methanol(500 L). The slurry was cooled to 10° C., water was added (500 L), andthe mixtrue was cooled to 0° C. The resulting precipitate was isolatedby filtration and dried under vacuum at 50° C. to afford 150 kg (85%) ofracemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoicacid as a white solid. DCI/MS: M+H⁺ at 426, 100%. M.P. 173-4° C. UVmaxima at 236 nm, 268 nm, and 353 nm.

Steps 7-8

A method for resolvingracemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoicacid is described in U.S. Pat. No. 5,498,716. In the first step of theresolution,racemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoicacid is reacted with a chiral compound to form a salt. A preferredchiral compound is (+)-ephedrine. In the second step, step 8 of Scheme1, the salt is reacted with a compound that aids in forming an amidebond. Examples of compounds that can be used to form an amide bond(i.e., amide forming reagents) are well known to those skilled in theart and include compounds that activate a carboxylic acid toward amideformation such as by conversion of the acid to an active ester, acidchloride, anhydride, etc. Examples of suitable regents include acidchlorides, acid anhydrides, chloroformates, thionyl chloride, phosphorusoxychloride, substituted carbodiimides, phosphoric acid, and the like.An especially preferred reagent is carbonyldiimidazole. It is noted thatsteps 7 and 8 can be run sequentially without isolation of intermediateproducts.

(+)-2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone(8)

A solution of2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoicacid (74.9 kg, 175.9 mol), (1S, 2R)-ephedrine hemihydrate (32.5 kg,186.5 mol), 200 proof ethanol (290 Kg) and water (17 L) were stirred andheated to about 35° C. for 35 minutes. The solution was filtered andthen cooled to about 20° C. until the onset of crystallization. Thereaction was further cooled to 0-5° C. for about 2 hours. Theintermediate ephedrine salt was filtered and washed with a cold (0-5°C.) solution of 200 proof ethanol (206 Kg) and water (10 L). Theephedrine salt was dissolved in 377 L of dichloromethane and stirredwith 125 L water and 9.7 kg 37% hydrochloric acid. The aqueous layer wasremoved. The organic layer was washed with water (125 L). The organiclayer was distilled to 60% of the original volume. Carbonyldiimidazolewas dissolved in CH₂Cl₂ (128 L) and slowly transferred to the reactionsolution. The reaction was complete after 20 minutes. The reaction waswashed two times with water (250 L each). The CH₂Cl₂ solution wasdistilled atmospherically, the volume being replaced with of 200 proofethanol (500 Kg). The ethanol solution was cooled at a rate of 20±5° C.per hour to 0-5° C. The solution was then held at 0-5° C. for 16 hours.The product was filtered and washed with 200 proof ethanol (100 kg). Theproduct was dried for 16 hours under vacuum at 60° C. This afforded 26.0Kg of(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinoneas a white solid (36% yield). ¹H-NMR: δ 8.87 (d, J=8.8, 1H), 8.61 (m,2H), 7.93 (d, J=7.0, 1H), 7.74 (m, 4H), 6.05 (m, 1H), 3.62 (m, 1H), 3.28(dd, J=7.0, 17.2, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J=6.2, 6H);CI (MS) M+1 at 408, 100%; [α]_(D) ²⁰=+135° (c=1, dichloromethane).

The resolution of racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinoneby ring opening, resolution with a resolving agent, and then ringclosure to give(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinoneis described in U.S. Pat. No. 5,498,716. Other resolution procedures,including resolving racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinonedirectly to(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinonewithout opening the lactam ring are known to those skilled in the art.Any resolution procedure is contemplated herein in conjunction with thesynthesis of racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.In other words, once racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinoneis made, various resolution procedures can be used by one skilled in theart to obtain(+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.

All documents referenced herein, including patents and patentapplications, are hereby incorporated by reference. The followingabbreviations are used herein.

-   Et₃N Triethylamine-   HOAc Acetic Acid-   DMF Dimethylformamide-   cat. Catalytic amount-   DME Dimethyl ether-   THF Tetrahydrofuran-   EtOH Ethanol-   CDI Carbonyldiimidazole-   MeOH Methanol-   MTBE Methyl tert-butyl ether-   MS Mass Spectra-   NMR Nuclear Magnetic Resonance-   DMSO Dimethylsulfoxide

1. A method of making 2-amino-7-hydroxy-1,8-naphthyridine sulfuric acidsalt, the method comprising the step of reacting 2,6-diaminopyridinewith malic acid and sulfuric acid to form2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt.
 2. A method ofmaking racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the method comprising the steps of: a) reacting2-amino-7-hydroxy-1,8-naphthyridine sulfuric acid salt with a phthalylreactant in a solvent to form phthalimidyl naphthyridine 2

b) reacting phthalimidyl naphthyridine 2 with a chlorinating agent toform chloride 3

c) reacting chloride 3 with a reducing agent to form hydroxyindolinone 4

d) reacting hydroxyindolinone 4 with a 5-methyl-2-oxo-hexyltriphenylphosphonium halide to form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.3. The method of claim 2 wherein in step a the phthalyl reactant isphthalic anhydride; in step b the chlorinating agent is phosphorusoxychloride; in step c the reducing agent is potassium borohydride; andin step d the 5-methyl-2-oxo-hexyl derivative is[(5-methyl-2-oxo)-hexyl]triphenylphosphonium bromide.
 4. A method ofmaking racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the method comprising the steps of: a) reacting phthalimidylnaphthyridine 2

with a chlorinating agent to form chloride 3

b) reacting chloride 3 with a reducing agent to form hydroxyindolinone 4

c) reacting hydroxyvindolinone 4 with a5-methyl-2-oxo-hexyltriphenylphosphonium halide to form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.5. A method of making racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the method comprising the steps of: a) reacting chloride 3

with a reducing agent to form hydroxyindolinone 4

b) reacting hydroxyindolinone 4 with a5-methyl-2-oxo-hexyltriphenylphosphonium halide to form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.6. A method of making racemic2-7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone,the method comprising the step of reacting hydroxyindolinone 4

with a 5-methyl-2-oxo-hexyltriphenylphosphonium halide to form racemic2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone.